Hellenic Society of Cardiology (2016) 57, 389e400

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REVIEW ARTICLE

Intravascular hemodynamics and coronary

artery disease: New insights and clinical
implications
Marina Zaromytidou a, Gerasimos Siasos a, Ahmet U. Coskun b,
Michelle Lucier a, Antonios P. Antoniadis a,
Michail I. Papafaklis a, Konstantinos C. Koskinas a,
Ioannis Andreou a, Charles L. Feldman a, Peter H. Stone a,*

a
Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United
States
b
Mechanical and Industrial Engineering, Northeastern University, Boston, MA, United States

Received 15 December 2015; accepted 26 July 2016

Available online 25 November 2016

KEYWORDS Abstract Intracoronary hemodynamics play a pivotal role in the initiation and progression of
Endothelial shear the atherosclerotic process. Low pro-inflammatory endothelial shear stress impacts vascular
stress; physiology and leads to the occurrence of coronary artery disease and its implications.
Atherosclerosis; ª 2016 Hellenic Society of Cardiology. Publishing services by Elsevier B.V. This is an open
Acute coronary access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
syndromes nc-nd/4.0/).

1. Introduction characterized by an early onset with a long interval before

The field of cardiovascular disease has experienced enor-
mous progress, but atherosclerotic coronary artery disease
(CAD) remains the leading cause of death. Atherosclerosis is
* Corresponding author. Peter H. Stone, Cardiovascular Division,
Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115,
United States. Tel.: þ1 8573071965; fax: þ1 8573071955.
E-mail address: pstone@partners.org (P.H. Stone).
Peer review under responsibility of Hellenic Society of
Cardiology.
clinical symptoms appear as well as heterogeneity in its
phenotypic expression and natural history. The identifica-
tion and control of coronary risk factors, such as diabetes,
smoking, arterial hypertension and hyperlipidemia, is the
cornerstone of preventative strategies.1 Atherosclerotic
lesions tend to form at certain arterial segments (e.g.,
branch points, curvatures, bifurcations, downstream of an
obstruction) despite the systemic effect of risk factors on
the vasculature, and only a small percentage of coronary
lesions lead to a clinical event. Therefore, local factors
must determine the localization and progression of the
atherosclerotic process. Extensive in-vitro and in-vivo

http://dx.doi.org/10.1016/j.hjc.2016.11.019
1109-9666/ª 2016 Hellenic Society of Cardiology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
390
studies concluded that intracoronary hemodynamics and
particularly flow-derived endothelial shear stress (ESS) are
the most prominent factors that underlie the diversity of
the natural history of atherosclerosis in susceptible in-
dividuals with CAD risk factors.
2. Hemodynamic factors affecting blood
vessels
2.1. Mechanical forces
Blood circulates through the vasculature following the
cardiac cycle. Vessel geometry alters the hemodynamic
characteristics, and changes in blood flow affect the
morphology and function of arteries. This constant inter-
action between blood flow and arterial geometry results in
the production of a complex hemodynamic pattern with
varying spatio-temporal characteristics.2e4
The metric used to quantify the biomechanical forces
induced by blood pressure and flow is called stress, and it is
defined as a force normalized by the area to which the
force is applied. Blood pressure-derived force, known as
tensile stress (TS), is distributed circumferentially to the
arterial wall, and it is represented by the Laplace’s law
equation (TSZP(r/h), where P is mean arterial blood
pressure, r is the lumen radius and h is vessel wall thick-
ness). Blood flow also produces tangential forces,5,6 which
is the friction of the flowing blood on the endothelial sur-
face, called endothelial shear stress (ESS), which is pro-
portional to the product of blood viscosity (m) and the
spatial gradient of blood velocity at the wall (ESS Z mdv/
dy) (Fig. 1). The arterial wall properties and structure
(arterial stiffness) also modify the impact of TS and ESS on
the lumen.7
Coronary blood flow, blood properties (primarily viscos-
ity) and arterial geometry determine the characteristics of
ESS. Laminar blood flow is characterized as smooth and
streamlined, and it is further categorized into disturbed or
undisturbed flow according to the presence or absence of
reverse flow, respectively.8,9 Arterial geometry determines
the ESS pattern formed. The presence of bifurcations,
branches, curves and obstructions modifies flow and ESS
Figure 1 Mechanical forces that impact the arterial wall.
SS Z shear stress, P Z arterial pressure, u Z blood velocity.
M. Zaromytidou et al.
patterns.10 Blood flow enters these lower pressure regions
and generates flow separation, recirculation and reat-
tachment zones (reverse flow), which is characterized as
low ESS (Fig. 2a). These disturbed flow zones are also
encountered upstream and downstream of obstructions,
such as stenotic atherosclerotic plaques, at stented lesions
and at coronary artery-vein graft junctions after a coronary
bypass surgery.11
Therefore, the complex interactions of blood flow, vis-
cosity and arterial geometry generate the different ESS
patterns that are characterized by their direction (unidi-
rectional, bidirectional) and magnitude (low, moderate,
high). Moderate ESS varies between 1.5 -3.0 Pa over the
cardiac cycle, and it is encountered in relatively straight
arterial segments, where it exhibits unidirectional flow
with atheroprotective effects. High ESS refers to values
over 3 Pa, which is present at the stenotic site of athero-
sclerotic plaques. Low ESS (below 1-1.5 Pa) with undis-
turbed unidirectional flow occurs at the inner areas of
curvatures and upstream of stenosis.12,13 Low oscillatory
ESS is characterized by bidirectional flow (reverse flow),
and it is observed at the ostia of branches, downstream of
stenotic plaques and at the lateral walls of bifurcations
(Fig. 2b). Low and/or oscillatory ESS promotes pro-
atherogenic pathways, and it is a key factor in the devel-
opment and progression of focal atherosclerosis.13,14
2.2. ESS and atherosclerosis
Atherosclerosis is a complex disease that involves various
components of normal arteries, such as endothelial cells,
smooth muscle cells (SMC) and arterial extracellular matrix
macromolecules, which undergo a phenotypic switch from
their normal physiological function under the stimulation of
local flow hemodynamics and inflammatory mechanisms.
There are several key points of the atherosclerotic process.
(1) The transportation, subendothelium accumulation/
retention and modification of low density lipoprotein (LDL)
particles that trigger the inflammatory cascade, activate
endothelial cells and signal the recruitment and migration
of monocytes into the endothelium. (2) The subsequent
differentiation of monocytes into macrophages that facili-
tates the phagocytosis of modified LDL and form foam cells
that amplify the inflammatory micro-environment, which
gradually progress into atherosclerotic lesions. (3) The
migration and differentiation of smooth muscle cells (SMCs)
to the intima that participating in all atherosclerotic stages
by altering extracellular matrix synthesis and releasing
cytokines and adhesion molecules involved in monocyte
recruitment and macrophage proliferation.15 Endothelial
shear stress is implicated in the regulation of all of these
critical steps, which supports its important role in athero-
sclerosis initiation and progression.
2.2.1. Mechanosensing and mechanotransduction
The endothelium plays a crucial role in the initiation and
progression stages of atherosclerosis because it is the bar-
rier between blood flow and arterial layers. Normal endo-
thelial cells sense changes in the microenvironment and
regulate important functions, such as vascular tone,
circulating cell adhesion, coagulation, fibrinolysis, and
vessel wall inflammation, in response to hemodynamic
Intravascular hemodynamics and coronary artery disease
Figure 2 (a) Types of blood flow, (b) distribution of ESS patterns along the length of an atherosclerotic lesion. NC Z necrotic
core.
changes. Endothelial cells are arranged in a specific manner
on the artery surface to form a tight seal, which controls
the transportation of all molecules between the lumen and
intima.
The identification of the different flow patterns
(mechanosensing) is mediated by numerous endothelial
mechanosensors, including ion channels, G-proteins, cav-
eolae, tyrosine kinase receptors, nicotinamide adenine
dinucleotide phosphate (NADPH), adhesion molecules
(PECAM-1/ VE-cadherin/ VEGFR2), primary cilium, integ-
rins, glycocalyx and the actin cytoskeleton. The detection
of shear stress stimuli leads to the physical deformation of
the cell surface, intracellular signal transmission and con-
version of the mechanical force into the chemical mole-
cules that generate the endothelial response via
differential gene expression (mechanotransduction).16,17
Laminar flow and unidirectional high shear stress create
an atheroprotective endothelial phenotype, and low/
oscillatory ESS is responsible for a proatherogenic pheno-
type. Different ESS patterns exert their gene modulation
via the anti-inflammatory transcription factor (TF) Kruppel-
like factor 2 (KLF2) and the proinflammatory nuclear fac-
tor-kB (NF-kB).18,19 The complex, partially understood
mechanisms of mechanosensing, mechanotransduction and
gene regulation translate the ESS stimuli and drive the
endothelium to respond by altering its cell conformation,
permeability and production of atheroprotective and
proatherogenic molecules.
Endothelial cell (EC) orientation and structure is modi-
fied according to blood flow types. Specifically, ECs exposed
to high ESS are elongated and aligned with laminar flow, but
low/oscillatory ESS leads to poorly aligned cells with
structural changes from fusiform to polygonal shapes. The
mitotic and endothelial apoptotic cell cycles are attenu-
ated in low/oscillatory ESS sites, which results in the
widening of cell-to-cell junctions, increases the
391
permeability of endothelial surface and facilitates the
infiltration of molecules.20
Stimuli for LDL internalization include the presence of
hyperlipidemia in combination with ESS-induced increased
endothelium permeability, the ESS-upregulated expression
of genes encoding for the LDL receptor of the endothelial
membrane, and the prolonged residence time of LDL par-
ticles near the endothelium due to low and oscillatory
ESS.13,21,22 Certain stimuli, including low ESS, signal the
migration of VSMCs from the media to the intima tunica,
where these cells proliferate and produce proteoglycans
that contribute to LDL retention, intimal thickening and
fibrous cap formation.9,23 Low ESS reverses the endothelial
microenvironment in favor of monocyte adherence and
migration by triggering the expression of adhesion mole-
cules on the endothelial cell membrane and the secretion
of chemoattractant cytokines to initiate the inflammatory
cascade.24
Retention of LDL results in its oxidation by reactive ox-
ygen species (ROS), which is upregulated in sites of low ESS
and augments inflammatory pathways (e.g., production of
inflammatory cytokines and adhesion molecules) and
endothelial dysfunction and triggers the differentiation of
monocytes into macrophages that encapsulate oxidized LDL
and form foam cells.25 ROS reduces the availability of NO,
which minimizes its anti-thrombotic, anti-mitogenic and
anti-inflammatory properties (e.g., prevention of LDL
oxidation and monocyte adhesion/transmigration into the
intima). Activation of endothelial nitric oxide synthase
(eNOS) only occurs in areas with physiological ESS, which
deprives regions with disturbed flow of the atheropro-
tective effects of NO.26,27
Vessel architecture is altered during atherosclerosis
progression, which leads to vascular remodeling. Low ESS
triggers the infiltration of macrophages into the
subendothelium-accumulated lipoproteins, which forms
392 M. Zaromytidou et al.

the necrotic lipid core that gradually grows in size and
inevitably disturbs arterial structure and geometry. The
production of extracellular matrix (ECM) molecules (e.g.,
collagen and elastin) from VSMCs and fibroblasts is normally
counterbalanced by the activity of matrix-degrading en-
zymes, primarily metalloproteinases (MMPs) and cathep-
sins, which maintain the integrity of the arterial wall. The
balance between ECM synthesis and degradation is dysre-
gulated in a low ESS milieu, which alters the arterial ar-
chitecture. The expression and activity of MMPs and
cathepsins is enhanced as dysfunctional endothelial cells
upregulate MMP and cathepsin gene expression.28 The
accumulation and activation of macrophages and VSMCs by
pro-inflammatory cytokines increases MMP release.29 Low
ESS interferes with VSMC function by promoting the
expression of growth factors that trigger the migration,
differentiation and proliferation of VSMCs and pro-
inflammatory cytokines, which halts ECM production and
signals VSMC apoptosis (Fig. 3).13 ESS also modifies the
arterial structure by promoting neovascularization (e.g.,
the upregulation of VEGF and other angiogenic stimuli) and
intraplaque hemorrhage.28,30,31
2.3. ESS and manifestations of coronary
atherosclerosis
Biomechanical factors substantially contribute to the for-
mation of vulnerable plaques and the actual event of pla-
que rupture or erosion.6,32 Atherosclerotic plaques are
formed by a lipid-rich necrotic core and a fibrous cap that
separates the core from the vessel lumen, which averts the
contact of the thrombogenic core compounds with blood
flow. Ruptured plaques are characterized by a weakened
fibrous cap that is susceptible to mechanical hemodynamic
forces, mostly tensile stress. The collagen concentration is
crucial for the fibrous cap to withstand these forces. The
increased proteolytic MMP function and decreased SMC
collagen synthesis in sites of low ESS may account for the
fibrous cap thinning that predisposes it to plaque rupture.
The excessive and expansive remodeling of the plaque in
sites of low ESS and intense MMP activity are associated
with plaque vulnerability.29,33,34 A large necrotic core is
associated with plaque rupture because of the anatomical-
mechanical changes it provokes and increased macrophage
infiltration are evident in rupture-prone plaques.35
The mechanisms responsible for plaque erosion are not
as well studied as the mechanisms responsible for plaque
rupture. Most of the erosions occur downstream of plaques,
where sites are typically subjected to low ESS. Low ESS
regions are characterized by increased endothelial cell
turnover, endothelial cell apoptosis and impairment of the
endothelial glycocalyx, which ultimately results in endo-
thelial denudation. Consequently, low ESS is involved in the
pathogenetic mechanism of erosion.20,36,37
The thrombogenic material of the necrotic core is
exposed to the bloodstream after rupture or erosion, which
results in thrombus formation that partially/totally oc-
cludes the lumen or remains contained in the vascular wall.
The factors that determine the impact of thrombus on the
vessel include the magnitude of the plaque cap disruption
and the blood thrombogenicity, which is increased in sites
with abnormal ESS values.38,39
3. In vivo techniques to investigate local ESS
The detrimental role of ESS in the initiation and progression
of atherosclerosis emphasizes the need for a validated tool
to assess ESS values in humans. ESS patterns depend on

Figure 3 Endothelial cells in a low ESS milieu signal the initiation and progression of the atherosclerotic process by affecting
important functions, such as vascular tone, circulating cell adhesion, coagulation, fibrinolysis and vessel wall inflammation.
LDL Z low density lipoprotein, ROS Z reactive oxygen species, MMPs Z matrix metalloproteinases, MCP Z monocyte chemo-
attractant protein, VCAM Z vascular cell adhesion molecule, ICAM Z intercellular adhesion molecule, TNF Z tumor necrosis
factor, IL Z interleukin, IFN Z interferon, BMP Z bone morphogenic protein, PDGF Z platelet-derived growth factor, VEGF Z -
vascular endothelial growth factor, ET Z endothelin, TGF Z transforming growth factor, NO Z nitric oxide, t-Pat tissue plas-
minogen activator, VSMCs Z vascular smooth muscle cells, SREBP Z sterol regulatory elements binding protein,
TFs Z transcription factors, NF-kB Z nuclear factor kappa-light-chain-enhancer of activated B cells.
Intravascular hemodynamics and coronary artery disease 393

coronary artery geometry and blood flow type, and an ac-
curate 3D reconstruction of the vessel geometry and coro-
nary blood flow values is a prerequisite for estimating ESS.
These particular data are derived using invasive imaging
modalities, such as intravascular ultrasound (IVUS) and
optical coherence tomography (OCT) after fusion with
coronary angiography, and noninvasive imaging tools, such
as coronary computed tomography angiography (CCTA).
The technology used to assess ESS has evolved tremen-
dously during the last decade. Assessments of ESS are not
performed in real time and require the transfer of imaging
data to laboratories with proper equipment and expertise,
but these factors are expected to change in the near
future.
3.1. Invasive techniques
The 3D reconstruction of the coronary artery after acqui-
sition of IVUS or OCT and x-ray angiography data are the
gold standards in ESS assessment because these techniques
are standardized and validated. Coronary angiography
produces a 2D outline of the arterial lumen throughout its
course on the epicardial surface that is not adequate for 3D
reconstruction without the addition of additional more
precise imaging modalities of the arterial wall and lumen.
Two angiographic images obtained from orthogonal views
are selected that correspond to the same coronary seg-
ments with the IVUS or OCT pullback. The lumen and EEM
borders are traced in each IVUS or OCT frame to facilitate
the extraction of the basic geometrical characteristics of
the vessel, which are subsequently oriented in 3D space
according to the angiographic information.40 The method-
ology for ESS assessments required pre-planned protocols
that utilize the IVUS catheter path to provide an accurate
orientation for the 3D model until recently. The introduc-
tion of the centerline method, which generates the 3D
reconstruction with the implementation of data derived
from routine coronary angiography and IVUS, simplifies the
procedure and allows the retrospective ESS interrogation of
imaging data banks.41
The second step in ESS assessment methods is the
calculation of coronary blood flow to the reconstructed 3D
artery. Coronary blood flow in the arterial section (a section
free of significant side branches that may alter the flow) is
calculated from the time required for the volume of blood
contained within the section to be displaced by radio-
opaque material during a contrast injection or via the use
of Doppler velocity measurements (Fig. 4).40,42,43

Figure 4 (A) Cross sectional OCT image with implemented local ESS values (lumen border), (B) Cross sectional IVUS image and (C)
Example of ESS and LAD coronary wall morphology after the 3D reconstruction and computational fluid dynamics. EEM Z external
elastic membrane, ESS Z endothelial shear stress, LAD Z left anterior descending, PaZ Pascal.
394
In an effort to further simplify ESS assessment, 3D artery
reconstruction may be generated using only information
from biplane angiography, a technique known as 3D quan-
titative coronary angiography (3D QCA).44,45 Although 3D
QCA is suggested as a less time-consuming and complicated
method, major drawbacks exist. Lumen area and vessel
diameter detection is far inferior to IVUS or OCT precision,
and the lack of its ability to provide information about
plaque components and vascular remodeling restricts its
use in ESS assessments.46,47
IVUS and OCT provide ESS assessments and plaque
characterization, but novel imaging modalities, such as
near-infrared spectroscopy (NIRS) / near-infrared fluores-
cence (NIRF), provide valuable information of plaque
composition and the possible role of inflammation.
3.1.1. Intravascular ultrasound
Intravascular ultrasound is an invasive modality that pro-
duces images of the arterial lumen and wall by converting
the reflected ultrasound waves into electrical signals. Its
axial resolution (70 to 200 mm) and penetration (>5 mm)
enables the evaluation of lumen dimensions, arterial
remodeling and PB that, combined with its good repro-
ducibility, supports IVUS as an effective modality for in-
vestigations of the natural history of atherosclerotic
disease. Certain limitations, such as the acoustic shadowing
in calcified plaques and the inability to characterize plaque
tissue components, led to the development of new tech-
niques, such as virtual histology IVUS (VH-IVUS) and OCT, to
address these issues. Virtual histology translates the IVUS
radiofrequency backscatter signal into tissue color images
(with each color signifying a precise tissue component),
which supplements the gray scale (IVUS) images and am-
plifies the available information. VH-IVUS exhibits excellent
predictive accuracies compared to histopathology samples,
but several studies in porcine models questioned its reliable
accuracy.48,49
3.1.2. Optical coherence tomography
Optical coherence tomography is an invasive imaging mo-
dality that generates cross-sectional images of the coronary
vessel using the reflections of near-infrared light. The
higher resolution (10-20 mm) of OCT compared to IVUS is
used to depict structures that are otherwise not well
characterized in IVUS images, such as thin fibrous cap,
thrombus and endothelial coverage of stent struts. OCT was
recently validated as a reliable modality for 3D coronary
artery reconstruction and assessment of ESS values because
of the more detailed and accurate imaging of coronary
vessels, including vulnerable plaques and intracoronary
devices. However, the inferior penetration depth of OCT
compared to IVUS into the arterial wall provides informa-
tion only for the superficial arterial layers and cannot
evaluate vascular remodeling or plaque burden (PB).46,50,51
3.1.3. Novel imaging modalities
IVUS and OCT are valuable imaging modalities for the
estimation of ESS and its association with the natural his-
tory of atherosclerosis. A hybrid IVUS-OCT catheter that
combines the imaging depth of IVUS with the high resolu-
tion of OCT has been developed and tested ex vivo with
promising results that await validation in human studies.52
M. Zaromytidou et al.
The combination of IVUS or OCT with the techniques of
near-infrared spectroscopy (NIRS) / near-infrared fluores-
cence (NIRF) also improves their imaging properties. Spe-
cifically, NIRS detects lipid core-containing plaques based
on the absorption and scatter patterns of near-infrared
light by the different plaque components.53e56 The addi-
tion of NIRS to IVUS/OCT catheters enhances the charac-
terization of plaque tissue regarding the lipid content, but
the limited penetration of NIRS (1-2 mm) is inadequate for
the study of deeper artery segments.53,57 The imple-
mentation of NIRF in invasive intracoronary plaque assess-
ment enables the study of the atherosclerotic mechanisms
on a cellular/molecular level and provides information on
inflammatory activity.58 Animal and ex vivo studies support
the introduction of NIRF to IVUS/OCT catheters as a
promising tool for the evaluation of the natural history of
atherosclerosis, but further technical improvements are
warranted to allow testing in human studies.59e61
3.2. Non-invasive techniques
CCTA has been used to reconstruct the 3D geometrical
model of the coronary artery for subsequent CFD analysis
and ESS calculations in an effort to minimize invasive
procedures and simplify the assessment of hemodynamic
parameters.62,63 A limited number of published data exist
on the estimation of ESS and plaque morphology using
CCTA, but the reported results are encouraging.64e66 The
non-invasive methodology of CCTA in ESS calculation
avoids the complications that accompany the intra-
coronary techniques and allows CCTA to be performed in
low and intermediate risk groups. However, the spatial
resolution (z400 mm) of CCTA cannot visualize small
diameter branches (<0.5 mm) or accurately identify
certain plaque or arterial wall characteristics and subtle
changes in atherosclerotic morphology, and the presence
of calcifications obscures lumen borders.67e70 Commercial
software for the quantification of PB exhibits good intra-
platform reproducibility, but industry standards should be
applied to overcome the poor interplatform
reproducibility.71
4. Role of ESS in the natural history of
atherosclerosis
The development of effective evaluation techniques uti-
lizing well validated and routinely used imaging modalities
paved the way for the in-vivo study of ESS in animal models
and humans. Understanding the role of ESS in CAD pro-
gression may be best accomplished with studies that are
designed to evaluate the ESS values and vessel morphology
in serial time points.
4.1. Animal studies
Animal studies to evaluate the natural history of athero-
sclerosis using ESS were performed in hypercholesterolemic
swine models because of the characteristic development of
human-like advanced atherosclerotic plaques. Animal
studies provide significant advantages of histopathological
analyses, which are the gold standard in plaque tissue
Intravascular hemodynamics and coronary artery disease
characterization, immunostaining and gene expression
measurement.
The results from the swine models support the detri-
mental role of low ESS in the initiation and progression of
atherosclerosis in the presence of systemic risk factors
(hyperlipidemia, hyperglycemia). Chatzizisis et al. demon-
strated that low ESS sites were associated with intense
subendothelium lipid accumulation, inflammation, severe
internal elastic lamina degradation, excessive expansive
remodeling and fibrous cap thinning.4 Koskinas et al.
examined the interaction between ESS and vascular
remodeling in a natural history study consisting of 5 time
points and provided new insights that low ESS was associ-
ated with the early initiation and the ongoing progression of
focal plaques. Vascular remodeling was a highly dynamic,
temporally changing response to local plaque formation.
Marked heterogeneity of remodeling patterns at each time
point was reported, and compensatory expansive remod-
eling was identified as the predominant vascular response.
Individual plaques also exhibit a heterogeneous course that
evolves through a variety of remodeling patterns
throughout their natural history while local ESS values
adapt to changes in vessel lumen and dimensions. Regions
of very low ESS resulted in plaques with excessive expansive
remodeling, which further exacerbated the low ESS envi-
ronment and augmented subsequent plaque progression.
Conversely, lesions with compensatory or constrictive
remodeling were characterized by an amelioration of the
adverse low ESS stimulus and a trend towards less marked
further growth. A small subpopulation of coronary segments
was exposed to a progressively worsening stimulus of low
ESS throughout their evolution, and these segments ulti-
mately evolved to presumed highest-risk plaques. These
high-risk lesions were identified in-vivo at earlier stages of
their natural history using the combined assessment of local
ESS, plaque thickness and vascular remodeling.34
Arterial regions exposed to low ESS exhibited reduced
endothelial cell coverage, augmented infiltration of acti-
vated inflammatory cells, and substantially increased
expression and enzymatic activity of elastolytic MMPs
relative to their inhibitors. These enzymes likely contribute
to the fragmentation of elastin fibers and promote the
excessive expansive remodeling response of the vessel wall,
which ultimately promotes the formation of atheromata
with thin fibrous caps.33 A similar serial study from a
different animal cohort complements the former results by
emphasizing the association of local low ESS with the for-
mation of lesions with reduced SMC content and augmented
expression and activity of collagenases, which favors
attenuated synthesis and increased catabolism of collagen.
This an imbalance likely contributes to the evolution of
early lesions to collagen-poor, thin-capped
atheromata.29,72
A recent study examined the association of ESS with
atherosclerotic initiation and progression by placing a ste-
notic shear modifying stent (SMS) in the coronary arteries of
mini-pigs and assessing ESS values using OCT. The results
supported previously published data of the presence of low
and multidirectional ESS downstream of SMS and associ-
ating these factors with plaque progression and TCFA
phenotype.67
395
Local and systemic factors must coexist for atheroscle-
rosis to initiate and progress, but the nature of their
interaction was not investigated until quite recently. Kos-
kinas et al. demonstrated that the pro-atherogenic
threshold of low ESS was cholesterol-dependent, with
increasing cholesterol levels exaggerating low ESS effects
and diminishing the atheroprotective effects of higher
ESS.73 The results of the animal studies support ESS as a key
factor in the mechanisms of atherosclerosis and highlight
the importance of local hemodynamic conditions in the
setting of systemic risk factors.
4.2. Human studies
4.2.1. Natural History of CAD
The first human studies were published approximately a
decade ago and demonstrated that ESS was a significant
determinant of atherosclerotic plaque progression and
vascular remodeling. Stone et al. reported that plaque
progression occurred almost exclusively in areas of low ESS
and may be accompanied by expansive or constrictive
remodeling.74,75 Subsequent studies by Samady et al. also
support the role of ESS in CAD associating low ESS with
plaque progression.76e78
These studies substantially contributed to elucidating
the role of ESS in atherosclerosis, but they are limited by
the small population number. The Prediction of Progression
of Coronary Artery Disease and Clinical Outcomes Using
Vascular Profiling of Shear Stress and Wall Morphology
(PREDICTION) Study was the largest serial anatomical nat-
ural history study of coronary atherosclerosis conducted in
506 Japanese patients who presented with an acute coro-
nary syndrome and underwent percutaneous coronary
intervention (PCI) at the culprit lesion followed by 3 vessel
imaging with IVUS and angiography. The positive predictive
value to predict clinically relevant obstruction progression
treated with PCI of baseline PB was estimated as 22% but
rose to 41% when the baseline pro-inflammatory low ESS
was considered. Further analyses, which included IVUS-
based tissue characteristics, revealed that the highest
positive predictive value (53%) and diagnostic accuracy
(88%) were demonstrated when low ESS and large necrotic
content were present. The negative predictive value
remained high (91%) if all predictors were absent (Fig. 5).79
Baseline low ESS was an independent predictor of plaque
progression and worsening luminal obstruction in routine
natural history of CAD and the development of clinically
relevant lesions treated with PCI. No association between
high ESS and plaque progression was observed. Very few
clinical events occurred in this low-risk Japanese patient
population. Therefore, an association between baseline
vascular characteristics and subsequent major adverse
clinical events could not be studied.80,81
The Providing Regional Observations to Study Predictors
of Events in the Coronary Tree (PROSPECT) study was a
natural history study of coronary atherosclerosis conducted
in 697 patients who presented with ACS in America and
Europe and were followed for a median period of 3.4 years.
This study provided an opportunity to examine the role of
low ESS in plaque progression in a truly high-risk popula-
tion. The non-culprit lesions associated with subsequent
396
Figure 5 Incidence of PCI for symptoms or plaque progression according to independent predictors- The PREDICTION study.
PB Z plaque burden, ESS Z endothelial shear stress, NC Z necrotic core, PCI Z percutaneous coronary intervention, PV Z pre-
dictive value.
major adverse cardiovascular events were characterized at
baseline by a large PB (70%), small minimal luminal area
(4.0 mm2) and the appearance of TCFA by radiofrequency
IVUS. The hazard ratio for major adverse cardiovascular
events at 3 years was high (11.05) if all 3 lesion charac-
teristics were present at baseline.82 Stone et al. investi-
gated the incremental prognostic role of low ESS in a post-
hoc analysis of the PROSPECT study to predict new MACE
and the anatomic characteristics in the high-risk Western
population of the PROSPECT study. The preliminary results
demonstrated that the presence of local low ESS within a
lesion provides substantial incremental prognostication for
future major adverse events when added to the other
known prognostic anatomic characteristics, an observation
highlighted by the fact that there were no MACE outcomes
in follow-up if the lesion did not exhibit local low ESS at
baseline regardless of PB, MLA, or lesion phenotype at
baseline.83
Recent serial natural history studies indicate that most
plaques also exhibit a highly variable natural history. Most
plaques, even advanced plaques, become quiescent over
time, but other plaques may evolve to become more highly
inflamed and more prone to rupture.34,84 The observation in
PROSPECT that <4% of large PB lesions and <5% of TCFA
histology lesions were associated with a new MACE support
the concept that the majority of even ostensibly high-risk
plaques generally become quiescent. In contrast, a non-
culprit lesion that remains in a low ESS microenvironment
will likely continue to progress whether it appears to be a
M. Zaromytidou et al.
TCFA or a ThCFA at the single baseline anatomical “snap-
shot” of imaging during the index culprit lesion event.
The recent implementation of high-resolution OCT in ESS
computation provides more detailed information on plaque
characteristics with respect to ESS value. One study in pa-
tients presenting with ACS used OCT and identified low ESS
areas that exhibited larger lipid accumulation, higher
prevalence of spotty calcification and macrophage density
compared to higher ESS regions. One interesting finding was
that low ESS plaques displayed thinner fibrous caps, and the
TCFA phenotype was present almost exclusively in low ESS
plaques, which confirms previous results from animal
studies. However, only a small percentage of low ESS le-
sions presented a TCFA phenotype, which suggests that a
multifactorial pattern defines plaque characteristics, in
which ESS plays a significant role. Notably, this study
investigated ESS and plaque morphology only at one time
point, and the variability in the natural history of individual
plaques was not evaluated.85
4.2.2. Role of Local ESS in Outcomes following Stent
Deployment
Several human studies focused on ESS assessment in inter-
ventional cardiology and stent deployment. Neointimal
formation, neoatherosclerosis and in-stent restenosis are
the nemeses of interventional cardiologists. ESS was
recently investigated as a parameter affecting prognosis
after stent implantation. Stent placement injures the
endothelium and arterial wall, which alters the local
Intravascular hemodynamics and coronary artery disease
geometry and blood flow (flow separation, recirculation).86
The development and implementation of drug-eluting
stents significantly reduced the formation of neointimal
hyperplasia compared to bare metal stents. Several studies
support the notion that ESS drives in-stent neointimal hy-
perplasia/ neoatherosclerosis and contributes to stent
failure, which stimulated the search for optimal stent po-
sition strategy and structure.87e89 ESS does not seem to
affect the arterial wall behind the struts, perhaps because
of the altered compressed arterial structure.87, 90 One
recent study stressed the importance of hemodynamic
factors in the neointimal response after Absorb bio-
resorbable vascular scaffold implantation, which motivates
studies for a more ergonomic stent design.87 The same
study group suggested that the interrogation of a stented
artery in terms of ESS should be performed with the fusion
of OCT and angiography because it is superior to IVUS/
angiography fusion.91
Important studies, such as PROSPECT and PREDICTION,
provided significant data on the natural history of athero-
sclerosis and validated results of smaller studies, but pieces
of the puzzle remain missing. The design of large human
studies that prospectively investigate the role of ESS in
atherosclerosis using imaging modalities with improved
resolution and penetration of plaque/tissue characteriza-
tion (e.g., IVUS/NIRS, OCT/IVUS, OCT/NIRF) would further
elucidate the pathophysiological mechanisms of CAD.92
5. Future plans/directions
Coronary hemodynamics and ESS are major determinants of
the natural history of atherosclerosis. The role of ESS in the
initiation of endothelial dysfunction, atherosclerosis,
vascular remodeling and plaque stability is well documented.
The identification of specific atherosclerotic plaques
that are prone to rupture or erosion and cause adverse
cardiovascular events is of the utmost importance. Early
stent placement or local drug delivery to vulnerable pla-
ques may prevent CAD complications. Unfortunately, the
level of evidence available is not sufficient to accurately
identify high-risk plaques. Studies that will fully elucidate
the complex role of pro-inflammatory low ESS in the tran-
sition of plaques from a stable to vulnerable phenotype and
translate the prognostic information in ESS mapping are
warranted.
The illuminating of ESS mechanisms may also provide
insights of the pleiotropic effects of various cardiovascular
medications or offer new therapeutic approaches using
drugs that target specific signaling pathways. Chronic
administration of valsartan or valsartan/ simvastatin in
animal models attenuates the proatherogenic effects of
low ESS independent of their antihypertensive and hypo-
lipidemic properties.93 Widely prescribed cardiovascular
regimens, such as statins and the b-blocker metoprolol,
seem to exert atheroprotective effects via attenuation of
the low ESS impact or restoration of atheroprotective ESS
values, respectively.94,95 However, the development of new
mechano-sensitive drug containers that are activated by
high shear stress to release the drug are being investigated
to provide a more prompt and effective treatment of acute
myocardial infarction and stroke.96
397
The techniques that are currently used to assess ESS are
primarily invasive and relatively time-consuming, which
restricts the study of ESS exclusively to the research field.
The introduction of newer techniques that overcome these
methodological limitations will allow a wider application
and study of ESS, which will deliver an invaluable body of
data and contribute enormously to an understanding of the
detailed mechanisms responsible for plaque progression
and ultimate disruption and inform new pre-emptive
interventions.
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